Cystic fibrosis (CF)isthemostcommonlethalinheriteddiseaseamongwhitepeople.ItisanautosomalrecessivediseasecausedbymutationsintheCFTR gene.Itischaracterizedbychronicbacteriallunginfection,progressivedeclineinlungfunction,andprematuredeathatanaverageageof38years.Morethan1000mutationsoftheCFTR genehavebeendescribed,but70%ofaffectedindividualshaveadeletionofphenylalanineatcodon508(ΔF508-CFTR)inatleastoneallele.ThismutationresultsinalackofCl− secretionandanincreaseinENaC-mediatedNa+ reabsorption,whichinturnresultsinareductioninthevolumeofthepericiliaryfluid.
DetailedstudyofthedifferentCFTR mutationshasresultedinanunderstandingofvariousdisease-relatedphenotypes,someofwhichareassociatedwithmilderdiseaseandsomewithmoreseveredisease.Sincethe1980s,researchfindingshaveelucidatedhowmanyofthemostcommonmutationsintheCFTR genecauseCF,andthishasledtothedevelopmentofdrugsthattargetspecificmutationsandreversethe individuals produce approximately 100 mL of mucus each day. Four cell types contribute to the quantity and composition of the mucus layer: goblet cells and Clara cells within the tracheobronchial epithelium, and mucous cells and serous cells within the tracheobronchial submucosal glands. Goblet cells, also referred to as surface secretory cells, represent approximately 15% to 20% of the tracheobronchial epithelium, and are found in the tracheobronchial tree up to the 12th division. In many respiratory diseases, goblet cells appear further down the tracheobronchial tree; thus the smaller airways are more susceptible to obstruction progressivereductioninlungfunction.Forexample,inonemutation(G551D-CFTR,whichaffects≈5%ofpatientswithCF),theCFTRCl− channelreachestheplasmamembraneofairwayepithelialcellsbutdoesnotsecreteCl− .Throughprecisionmedicine,adrug,ivacaftor(Kalydeco),hasbeenfoundtostimulateCl− secretionviatheG551D-CFTR,therebyimprovinglungfunctionanddecreasingtherateofdiseaseprogression.WhentheallelesarehomozygousfortheΔF508CFTRmutation(whichaffects≈50%ofpatientswithCF),theCFTRCl− channeldoesnotreachtheplasmamembraneofairwayepithelialcells.
In2015,theU.S.FoodandDrugAdministrationapprovedacombinationdrugtherapy,lumacaftor/ivacaftor(Orkambi),thathasbeenshowntocorrectthegenedefect,increasetheamountofΔF508-CFTRintheplasmamembrane,andimproveCl− transport.Clinically,bothivacaftorandlumacaftor/ivacaftorhavebeenshowntoimprovelungfunctionsignificantlyandtodecreasetherateofdeclineinlungfunction.
by mucus plugging. Goblet cells secrete neutral and acidic glycoproteins rich in sialic acid in response to chemical stimuli. In the presence of infection or cigarette smoke or in patients with chronic bronchitis, goblet cells can increase in size and number, extend above the 12th division of the tracheobronchial tree, and secrete copious amounts of mucus. Injury and infection increase the viscosity of the mucus secreted by goblet cells, which reduces mucociliary clearance of inhaled particles and pathogens.